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J Neurol Neurosurg Psychiatry 2000;68:405–415 405

NEUROLOGICAL ASPECTS OF TROPICAL DISEASE

Japanese encephalitis
Tom Solomon, Nguyen Minh Dung, Rachel Kneen, Mary Gainsborough,
David W Vaughn, Vo Thi Khanh

Although considered by many in the west to be West Nile virus, a flavivirus found in Africa, the
a rare and exotic infection, Japanese encephali- Middle East, and parts of Europe, is tradition-
tis is numerically one of the most important ally associated with a syndrome of fever
causes of viral encephalitis worldwide, with an arthralgia and rash, and with occasional
estimated 50 000 cases and 15 000 deaths nervous system disease. However, in 1996 West
annually.1 2 About one third of patients die, and Nile virus caused an outbreak of encephalitis in
half of the survivors have severe neuropshychi- Romania,5 and a West Nile-like flavivirus was
atric sequelae. Most of China, Southeast Asia, responsible for an encephalitis outbreak in
and the Indian subcontinent are aVected by the New York in 1999.6 7
virus, which is spreading at an alarming rate. In In northern Europe and northern Asia, flavi-
these areas, wards full of children and young viruses have evolved to use ticks as vectors
adults aZicted by Japanese encephalitis attest because they are more abundant than mosqui-
Department of to its importance. toes in cooler climates. Far eastern tick-borne
Neurological Science,
University of encephalitis virus (also known as Russian
Liverpool, Walton Historical perspective spring-summer encephalitis virus) is endemic
Centre for Neurology Epidemics of encephalitis were described in in the eastern part of the former USSR, and
and Neurosurgery, Japan from the 1870s onwards. Major epidem- Western tick-borne encephalitis virus occurs in
Fazakerley, Liverpool Europe and has caused recent epidemics in
L9 7LJ, UK
ics were reported about every 10 years, with
more than 6000 cases reported in the 1924 Germany and Austria.8 In the United Kingdom
Tom Solomon
epidemic.3 The term type B encephalitis was the tick borne Louping Ill virus is is enzootic in
Liverpool School of originally used to distinguish these summer sheep, and occasionally causes encephalitis in
Tropical Medicine, epidemics from von Economo’s encephalitis sheep and humans.9
Pembroke Place, lethargica (sleeping sickness, known as type A),
Liverpool L3 5QA, UK
Tom Solomon
but the B has since been dropped. In 1933 a ENZOOTIC CYCLE
filterable agent was transmitted from the brain Japanese encephalitis virus is transmitted natu-
Centre for Tropical of a fatal case to cause encephalitis in monkeys; rally between wild and domestic birds, and pigs
Diseases, Cho Quan the prototype Nakayama strain of Japanese by Culex mosquitoes—the most important for
Hospital, Ho Chi Minh encephalitis virus was isolated from the brain of human infection being Culex tritaeniorrhynchus
City, Vietnam a fatal case in 1935. The virus was later classed which breeds in pools of stagnant water (such
Nguyen Minh Dung
Mary Gainsborough
as a member of the genus Flavivirus (family as rice paddy fields).10 Although many animals
Vo Thi Khanh Flaviviridae) named after the prototype yellow can be infected with the virus, only those which
fever virus (Latin; yellow=flavi). Although of develop high viraemias are important in the
Royal Liverpool no taxonomic significance, the ecological term natural cycle. As well as maintaining and
Children’s NHS Trust, arbovirus is often used to describe the fact that amplifying Japanese encephalitis virus in the
Alder Hey, Liverpool Japanese encephalitis virus is insect (arthro- environment, birds may also be responsible for
L12 2AP, UK
Rachel Kneen
pod) borne. the spread to new geographical areas. Pigs are
the most important natural host for transmis-
Centre for Tropical Epidemiology sion to humans, because they are often kept
Medicine and NEUROTROPIC FLAVIVIRUSES: A GLOBAL close to humans, have prolonged and high
Infectious Diseases, PERSPECTIVE viraemias, and produce many oVspring—thus
NuYeld Department providing a continuous supply of previously
of Clinical Medicine,
Japanese encephalitis virus is transmitted
John RadcliVe between animals by Culex mosquitoes, and uninfected new hosts. The virus does not typi-
Hospital, Headington, occurs across eastern and southern Asia and cally cause encephalitis in these natural hosts,
Oxford, OX3 9DU, UK the Pacific rim. However, related neurotropic athough abortions occur in pregnant sows.
Mary Gainsborough flaviviruses are found across the globe (fig 1);
they share many virological, epidemiological, EPIDEMIOLOGY OF HUMAN DISEASE
Department of Virus
Diseases, Walter Reed
and clinical features.2 Molecular virological Humans become infected with Japanese en-
Army Institute of studies suggest that all flaviviruses derived cephalitis virus coincidentally when living or
Research, Washington, from a common ancestor some 10–20 000 travelling in close proximity to the enzootic
DC 20307, USA years ago, and are rapidly evolving to fill cycle of the virus. Although most cases occur in
David W Vaughn ecological niches.4 Examples of mosquito rural areas, Japanese encephalitis virus is also
borne neurotropic flaviviruses include Murray found on the edge of cities. Epidemiological
Correspondence to:
Dr Tom Solomon Valley encephalitis virus in Australia, and St studies have shown that after the monsoon
tom.solomon@virgin.net Louis encephalitis virus in North America. rains mosquitoes breed prolifically, and as their
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406
Figure 1 Map showing approximate global distribution of major neurotropic flaviviruses; JE=Japanese encephalitis; MVE=Murray valley encephalitis;
WN=West Nile; WTBE=Western tick-borne encephalitis; FETBE=Far Eastern tick-borne encephalitis; LI=Louping Ill virus; SLE=St Louis encephalitis.
numbers grow, so does their carriage of
Japanese encephalitis virus and the infection
rate of pigs.11 12 Human infection soon follows.
In sentinel studies, previously unexposed pigs
placed in endemic areas were infected with the
virus within weeks.
Although the virus has occasionally been
isolated from human peripheral blood13 virae-
mias are usually brief and titres low; thus
humans are considered a dead end host from
which transmission does not normally occur.
Cross sectional serological surveys have shown
that in rural Asia most of the population are
infected with Japanese encephalitis virus dur-
ing childhood or early adulthood.14 About 10%
of the susceptible population is infected each
year.15 However, most infections of humans are
asymptomatic or result in a non-specific
flu-like illness; estimates of the ratio of sympto-
matic to asymptomatic infection vary between
1 in 2516 and 1 in 1000.17
Japanese encephalitis is mostly a disease of
children and young adults. In northern Thai-
land the incidence has been estimated to be up
to 40 per 100 000 for ages 5 to 25, declining to
almost zero for those over 3514 18 The incidence
is lower among young children (<3 years old)
than in older children, possibly reflecting
behavioural factors—for example, playing out-
side after dusk.19
When epidemics first occur in new locations,
such as in Sri Lanka, India, and Nepal, adults
Solomon, Dung, Kneen, et al
are also aVected.20 The susceptibility of immu-
nologically naive adults was also demonstrated
by the incidence of Japanese encephalitis
among American troops during conflicts in
Japan, Korea, and Vietnam21–25 The rate of
symptomatic infection was higher in these
troops than in local populations. This may be
explained by partial protection due to previous
flavivirus exposure in the indigenous popula-
tion, age related diVerences, diVerent genetic
susceptibility to Japanese encephalitis, or more
sensitive disease surveillance among United
States troops.
Broadly speaking two epidemiological pat-
terns of Japanese encephalitis are recognised.19
In northern areas (northern Vietnam, northern
Thailand, Korea, Japan, Taiwan, China, Nepal,
and northern India) huge epidemics occur
during the summer months, whereas in south-
ern areas (southern Vietnam, southern Thai-
land, Indonesia, Malaysia, Philippines, Sri
Lanka, and southern India) Japanese encepha-
litis tends to be endemic, and cases occur spo-
radically throughout the year with a peak after
the start of the rainy season.19
Various explanations for this diVerent pat-
tern have been oVered. The finding that
Japanese encephalitis virus isolates from epi-
demic northern Thailand and endemic south-
ern Thailand were of diVerent genotypes (see
below) led to the suggestion that diVering neu-
rovirulence among diVerent strains may be
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Japanese encephalitis 407

25 remains high through the year, the number of

A
cases each month is constant. In the north a
sharp rise in cases of Japanese encephalitis
20 during the summer months corresponds with a
rise in temperature above 20°C. The prolonged
mosquito larval development time and longer
15 extrinsic incubation period of Japanese en-
cephalitis virus at cooler temperature, which
%

thus reduce the rate of virus transmission,

10 could be one explanation for these findings.

GEOGRAPHICAL DISTRIBUTION

5 In the past 50 years the geographical area

aVected by Japanese encephalitis virus has
expanded (fig 1). DiVerences in diagnostic
0
capabilities and in reporting of encephalitis
make it impossible to plot this expansion
precisely. However, the timing of the first
35 B reported cases or new epidemics in each area
gives an impression of the relentless spread of
30 Japanese encephalitis. In China outbreaks of
summer encephalitis occurred from 1935, and
25 the virus was first isolated there in 1940; there
are currently 10–20 000 cases a year, although
20 in the early 1970s it was over 80 000 cases
annually.19 In the far eastern Russian states,
°C

Japanese encephalitis first occurred in 1938. In

15
1949, large epidemics were reported from
South Korea for the first time. Epidemics in
10 Hanoi
northern Vietnam followed in 1965 (currently
Ho Chi Minh City 1000–3000 cases nationally a year), and in
5 Chiang Mai in northern Thailand in 1969
(currently 1500–2500 cases nationally a year).
0 Japanese encephalitis was recognised in south-
ern India from 1955, but was confined to the
400
south until the 1970s. Since then, large
C outbreaks (2000–7000 cases a year) have been
350 reported from eastern and northeastern states.
The fact that adults and children were equally
300 aVected in these Indian states strongly sup-
ports the idea that the virus was introduced
250 here for the first time. The late 1970s also saw
the first cases in Burma and Bangladesh, and
mm

200 large epidemics (up to 500 cases a year) in

southwestern Nepal. In 1985 Sri Lanka experi-
150 enced its first epidemic with 410 cases and 75
deaths. Japanese encephalitis virus continues to
100 spread west with cases occurring in Pakistan28
and new epidemics in the Kathmandu valley of
50 Nepal.29
Charting the progression of the disease
0
southeast across Asia and the Pacific rim is
Mar

May
Jan

Feb

Apr

Jun

Jul

Aug

Sep

Oct

Nov

Dec

harder because sporadic cases in endemic areas

Figure 2 Relation between (A) encephalitis cases, (B) temperature, and (C) rainfall in
Ho Chi Minh city (southern Vietnam), and Hanoi (northern Vietnam). (Source:
National Institute of Health and Epidemiology, Hanoi, and Pasteur Institute, Ho Chi
Minh City.)
responsible.26 However, data from Vietnam do
not support this: isolates of the virus from epi-
demic northern Vietnam were the same
genotype as those from endemic southern
Vietnam.27 Comparisons of climatic data from
northern and southern Vietnam suggest that
temperature may be important (fig 2). Whereas
rainfall patterns are almost identical in north-
ern and southern Vietnam, the temperature is
very diVerent, and the number of cases of
encephalitis seems to follow temperature
closely. In the south, where the temperature
do not command the same attention as the mas-
sive epidemics that occur in temperate climates.
The disease has occurred on the western Pacific
islands with outbreaks in Guam in 194730 and
Saipan in 1990.31 In Malaysia the disease is
endemic; the virus was first isolated in the 1960s
and about 100 cases are recorded annually. The
epidemiology has recently been complicated by
a superimposed epidemic of a previously uni-
dentified encephalitic virus. This RNA para-
myxovirus (named Nipah virus) is similar to the
Australian Hendra virus and seems to be trans-
mitted to humans (especially abattoir workers
and farmers) from the bodily fluid of pigs.32–34
Japanese encephalitis is endemic in Indonesia,
and 1000–2500 cases of encephalitis are
reported annually, although in most the
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408
aetiological agent is not confirmed.35 Further
east, Japanese encephalitis occurs sporadically
in the Philippines and New Guinea. The first
cases occurred in the Australian Torres Straits
islands in 1995,36 and it was reported for the
first time north of Cairns on the Australian
mainland in 1998.37 38
The reasons for the spread of Japanese
encephalitis are incompletely understood, but
probably include changing agricultural prac-
tices, such as increasing irrigation (which
allows mosquito breeding), and animal hus-
bandry (which provides host animals). In
Indonesia, the lower prevalence of antibody to
Japanese encephalitis virus in Borneo than
neighbouring Bali has been attributed to the
lack of pigs in this predominantly Moslem
culture.35 In developed countries such as Japan,
Taiwan, and South Korea the number of cases
has fallen, probably due to a combination of
mass vaccination of children, spraying of pesti-
cides, changing pig rearing practices, separa-
tion of housing from farming, better housing
with air conditioning, and less availability of
mosquito breeding pools.10 However, in Korea
the widespread use of vaccine in children has
been associated with a higher incidence of
Japanese encephalitis in those over 15 years.19
Virology
In common with all flaviviruses, Japanese
encephalitis virus has a small (50 nm) lipopro-
tein envelope surrounding a nucleocapsid
comprising of core protein and 11 kb single
stranded RNA (3800 kD). At least five
genotypes of Japanese encephalitis virus occur
in Asia, which relate roughly to the geographi-
cal area of isolation.26 39 The complete nucle-
otide sequence has been published, and
includes 5' and 3' untranslated regions, and a
Figure 3 Staring mask-like facies due to a wide palpebral angle in two Vietnamese children with Japanese encephalitis.
(T Solomon.)
Solomon, Dung, Kneen, et al
single open reading frame encoding genes for
three structural proteins (capsid protein (C);
precursor to the membrane M protein (PrM);
and envelope protein (E)) and seven non-
structural proteins. The search for genetic
determinants of virulence in animal models of
flavivirus encephalitis has focused on the E
protein.40 This protein, of about 500 amino
acids, is the major component of the surface
projections of the virion. As well as eliciting
neutralising antibodies and protective immune
responses in the host41 42 it is thought to be the
cell receptor binding protein and mediator of
membrane fusion and cell entry.43 A highly
sulphated heparan sulphate molecule has
recently been identified as the putative recep-
tor of flavivirus cell entry.44 Various ap-
proaches have allowed E gene sequences of
flaviviruses to be related to virulence in animal
models. These suggest that the E protein has a
major role in determination of virulence
phenotype, and that single amino acid substi-
tutions are suYcient to cause loss of neuro-
virulence or neuroinvasiveness.45–47 Whether
such diVerences are important in determining
the clinical presentation of Japanese encepha-
litis virus in humans is unknown.
Clinical features
Patients with Japanese encephalitis typically
present after a few days of non-specific febrile
illness, which may include coryza, diarrhoea,
and rigors.2 This is followed by headache, vom-
iting, and a reduced level of consciousness,
often heralded by a convulsion. In some
patients, particularly older children and adults,
abnormal behaviour may be the only present-
ing feature, resulting in an initial diagnosis of
mental illness. For example, during the Korean
conflict some American servicemen with
 Downloaded from http://jnnp.bmj.com/ on March 10, 2015 - Published by group.bmj.com
Japanese encephalitis
Figure 4 Facial grimacing in a Vietnamese boy with Japanese encephalitis. (T Solomon.)
Japanese encephalitis were initially diagnosed
as having “war neurosis”.23
A proportion of patients make a rapid sponta-
neous recovery (so called abortive encephalitis).
Others may present with aseptic meningitis and
have no encephalopathic features.48 Convulsions
occur often in Japanese encephalitis, and have
been reported in up to 85% of children49 and
10% of adults.22 50 In some children a single
convulsion is followed by a rapid recovery of
consciousness, resulting in a clinical diagnosis of
febrile convulsion. Generalised tonic-clonic sei-
zures occur more often than focal motor
seizures. Multiple or prolonged seizures and sta-
tus epilepticus are associated with a poor
outcome (Solomon T et al, unpublished obser-
vations). In a proportion of children subtle
motor seizures occur, causing twitching of a
digit, eye, or mouth, eye deviation, nystagmus,
excess salivation, or irregular respiration. With-
out electroencephalographic monitoring these
may be diYcult to identify (Solomon T et al,
unpublished observations).
The classic description of Japanese encepha-
litis includes a dull flat mask-like facies with
wide unblinking eyes (fig 3), tremor, general-
ised hypertonia, and cogwheel rigidity. These
features were reported in 70%-80% of Ameri-
can service personnel, and 20%-40% of Indian
children.48 49 Opisthotonus and rigidity spasms,
particularly on stimulation, occur in about
15% of patients and are associated with a poor
prognosis.48 49 Other extrapyramidal features
include head nodding and pill rolling move-
ments, opsoclonus myoclonus, choreoatheto-
sis, and bizarre facial grimacing, and lip
smacking (fig 4).48 49 51 Upper motor neuron
facial nerve palsies occur in around 10% of
children and may be subtle, or intermittent.
Changes of respiratory pattern, flexor and
extensor posturing, and abnormalities of the
pupillary and occulocephalic reflexes are poor
prognostic signs.48 49 52 and may reflect en-
cephalitis in the brain stem.10 However in some
patients a clear rostrocaudal progression of
brainstem signs, an association with high CSF
opening pressures, and a reversal of signs on
aggressive management of raised intracranial
pressure suggests that transtentorial herniation
may also contribute.(Solomon T et al, unpub-
lished observations)
ACUTE FLACCID PARALYSIS
Recently we have identified a subgroup of
patients infected with Japanese encephalitis
409
virus who presented with a poliomyelitis-like
acute flaccid paralysis.53 After a short febrile
illness there was a rapid onset of flaccid paraly-
sis in one or more limbs, despite a normal level
of consciousness. Weakness occurred more
often in the legs than the arms, and was usually
asymmetric. Thirty per cent of such patients
subsequently developed encephalitis, with re-
duced level of consciousness, and upper motor
neuron signs, but in most acute flaccid paraly-
sis was the only feature. At follow up (1–2 years
later) there was persistent weakness and
marked wasting in the aVected limbs. Nerve
conduction studies demonstrated markedly
reduced motor amplitudes, and EMG showed
a chronic partial denervation, suggesting ante-
rior horn cell damage.53 Flaccid paralysis also
occurs in comatose patients with “classic”
Japanese encephalitis, being reported in
5%-20%.22 54 Electrophysiological studies have
confirmed anterior horn cell damage, and MRI
of the spinal cord showed abnormal signal
intensity on T2 weighted images.55 Occasion-
ally respiratory muscle paralysis may be the
presenting feature.56
OUTCOME
About 30% of patients admitted to hospital with
Japanese encephalitis die, and around half of the
survivors have severe neurological sequelae.
However, in areas with better hospital facilities
there is a reduction in mortality, but a concomi-
tant increase in the number of patients with
sequelae.2 About 30% of survivors have frank
motor deficits. These include a mixture of upper
and lower motor neuron weakness, and cerebel-
lar and extrapyramidal signs.24 57 Fixed flexion
deformities of the arms, and hyperextension of
the legs with “equine feet” are common (fig 5).
Twenty per cent of patients have severe cognitive
and language impairment (most with motor
impairment also), and 20% have further
convulsions.58 59 A higher rate of sequelae is
reported for children than adults.60 In addition,
more detailed studies have shown that about half
of those who were classed in the good recovery
group have more subtle sequelae such as learn-
ing diYculties, behavioural problems, and subtle
neurological signs.58
INVESTIGATIONS
A peripheral neutrophil leukocytosis is seen in
most patients, and hyponatraemia may occur as
a consequence of inappropriate antidiuretic
hormone secretion (SIADH). The CSF opening
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410
Figure 5 Fixed flexion of the upper limb: a common
sequelae in Japanese encephalitis.
pressure is increased in about 50% of patients.
High pressures (>250 mm) are associated with
a poor outcome (Solomon T et al, unpublished
observations). Typically there is a moderate
CSF pleocytosis of 10–100 cells/mm3, with
predominant lymphocytes, mildly increased
protein (50–200 mg%), and a normal glucose
ratio. However, polymorphonuclear cells may
predominate early in the disease, or there may
be no CSF pleocytosis.49
In about 50% of patients CT shows bilateral
non-enhancing low density areas in one or
more of the thalamus, basal ganglia, midbrain,
pons, and medulla.61 62 Magnetic resonance
imaging is more sensitive, typically demon-
strating more extensive lesions, (typically high
signal intensity on T2 weighted images) of the
thalamus, cerebral hemispheres, and
cerebellum.55 63 Thalamic lesions of mixed
intensity may also be seen on T1 and T2
weighted scans suggesting haemorrhage.51 55
Imaging studies may be useful in distinguishing
Japanese encephalitis from herpes simplex
encephalitis, where the changes are character-
istically frontotemporal.64 However, most re-
ports are of scans performed late in the illness,
and the diagnostic value of scans performed
early is unknown. Single photon emission tom-
ography (SPECT) studies carried out acutely
may show hyperperfusion in the thalamus and
putamen.65 Follow up studies have shown
hypoperfusion in the same areas, as well as in
the frontal lobes.51
Various electroencephalographic abnor-
malities have been reported in Japanese
encephalitis including theta and delta coma,
burst suppression, epileptiform activity,
and occasionally alpha coma.62 66 DiVuse
slowing may be useful in distinguishing
Japanese encephalitis from herpes simplex
virus, in which changes are characteristically
Solomon, Dung, Kneen, et al
frontotemporal.64 Measurement of evoked
potentials shows delays of central motor
conduction times consistent with widespread
involvement at the cortical and subcortical
levels.62
The diVerential diagnosis of Japanese en-
cephalitis is broad and includes other viral
encephalitides (arboviruses, herpes viruses,
enteroviruses, and postinfectious and postvac-
cination encephalomyelitis), other CNS infec-
tions (bacterial and fungal meningitis, tubercu-
losis, cerebral malaria, leptospirosis, tetanus,
abscesses), other infectious diseases with CNS
manifestations (typhoid encephalopathy,
febrile convulsions), and non-infectious diseases
(tumours, cerebrovascular accidents, Reye’s
syndrome, toxic and alcoholic encephalopathies,
and epilepsy).2 10 Where other flaviviruses circu-
late they should also be included in the diVeren-
tial. Even viruses which are not traditionally
considered as neurotropic may cause CNS
disease, and only with appropriate diagnostic
tests can viruses such as West Nile virus and
dengue viruses be distinguished from Japanese
encephalitis virus.67 67a
DIAGNOSIS
Attempts to isolate Japanese encephalitis virus
from clinical specimens are usually unsuccess-
ful, probably because of low viral titres and the
rapid production of neutralising antibodies.
Isolates may sometimes be obtained from CSF
(in which case it is associated with a failure of
antibody production and a high mortality
rate)68 or from brain tissue (either at necropsy
or postmortem needle biopsy). Immunohisto-
chemical staining of CSF cells or necropsy tis-
sue with anti- Japanese encephalitis virus poly-
clonal antibodies may be positive.69 70 However,
for most practical purposes Japanese encepha-
litis is diagnosed serologically. The haema-
glutination inhibition test was used for many
years, but it had various practical limitations,
and as it required paired serum, could not give
an early diagnosis.71 In the 1980s IgM and IgG
capture enzyme linked immunosorbant assays
(ELISAs) were developed which have become
the accepted standard for diagnosis of Japanese
encephalitis.72 73 After the first few days of
illness, the presence of anti-Japanese encepha-
litis virus IgM in the CSF has a sensitivity and
specificity of >95% for CNS infection with the
virus (before this false negatives may occur).74
However, because ELISAs require complex
equipment, their use has been confined largely
to a few academic or referral centres, rather
than the rural areas where Japanese encephali-
tis occurs. Recently the IgM ELISA has been
modified to a simple nitrocellulose membrane
based format in which the result is a colour
change visible to the naked eye.75 This test,
which is rapid, simple to use, and requires no
specialised equipment should prove useful for
diagnosis of the disease in rural hospitals. Japa-
nese encephalitis virus RNA has been detected
in human CSF samples using the reverse tran-
scriptase polymerase chain reaction28 76; how-
ever, its reliability as a routine diagnostic test
has yet to be shown.
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Japanese encephalitis
Pathogenesis
Only about 1 in 25 to 1 in 1000 humans
infected with Japanese encephalitis virus de-
velop clinical features of infection.16 17 19 These
may range from a mild flu-like illness to a fatal
meningoencephalomyelitis. The factors deter-
mining which of all the humans infected
develop disease are unknown, but could
include viral factors such as route of entry,
titre, and neurovirulence of the inoculum, and
host factors such as age, genetic make up, gen-
eral health, and pre-existing immunity.
After the bite of an infected mosquito, the
virus is thought to amplify peripherally, causing
a transient viraemia before invading the CNS.
Based on data from mice and macaque
monkeys, the site of peripheral amplification is
thought to be dermal tissue and then lymph
nodes. The means by which Japanese encepha-
litis virus crosses the blood-brain barrier is
unknown. In experimental studies with a ham-
ster model of St Louis encephalitis virus (a
related flavivirus) the olfactory route was
shown to be important.77 Intranasal spraying is
also an eVective means of experimentally
inoculating monkeys.78 However, immuno-
histochemical staining of human postmortem
material has shown diVuse infection through-
out the brain, indicating a haematogenous
route of entry.70 79 Although experimental
evidence suggests that replication within en-
dothelial cells may be an important means of
crossing the blood-brain barrier in some
flaviviruses, for Japanese encephalitis virus
passive transfer across the endothelial cells
seems a more likely mechanism.80 81 Other fac-
tors which compromise the integrity of the
blood-brain barrier have also been implicated
as risk factors for neuroinvasion. In several
studies a disproportionate number of fatal
cases had neurocysticercosis at necropsy.82 83 It
has also been suggested that head trauma (for
example, due to a road traYc accident) during
the transient viraemia could facilitate viral
entry into the CNS.84
Electron microscopic studies of the brains of
infected mice show that the virus replicates in
the rough endoplasmic reticulum and golgi
apparatus. There is hypertrophy of the endo-
plasmic reticulum and degeneration into cyctic
structures causing extensive dysfunction.85
HISTOPATHOLOGY
At necropsy, CNS findings in Japanese en-
cephalitis reflect the inflammatory response to
widespread neuronal infection with virus.3 79 86
The leptomeninges are normal or hazy. The
brain parenchyma is congested with focal
petechiae or haemorrhage in the grey matter.
When survival is prolonged beyond 7 days
blotchy necrolytic zones are seen. The white
matter usually appears normal. In some
patients, the grey matter of the spinal cord is
confluently discoloured, resembling that of
poliomyelitis.87 The thalamus, basal ganglia,
and midbrain are heavily aVected, providing
anatomical correlates for the tremor and
dystonias which characterise Japanese en-
cephalitis. At the histological level, invasion of
neurons by Japanese encephalitis virus is
411
followed by perivascular cuYng, infiltration of
inflammatory cells (T cells and macrophages)
into the parenchyma, and phagocytosis of
infected cells.3 79 T cells in the brains of fatal
cases stained with monoclonal antibodies are
CD8+ and CD8- (presumed to be CD4+) and
are localised at the perivascular cuV. Both cell
types are found in the CSF in acute infection,
though the predominant cell type is CD4+.79 In
patients that die rapidly, there may be no histo-
logical signs of inflammation, but immuno-
histochemical studies disclose viral antigen in
morphologically normal neurons.79 88 This may
explain the normal CSF findings in a pro-
portion of patients with Japanese encephalitis.
IMMUNOLOGY
Interferon and interferon inducers are active
against Japanese encephalitis virus in mice and
monkeys,89 90 and endogenous interferon-á has
been detected in the plasma and CSF of
humans with Japanese encephalitis.91 In addi-
tion both humoral and cellular immune
responses occur after infection with Japanese
encephalitis virus. The humoral immune re-
sponse in Japanese encephalitis has been well
characterised. When disease is due to primary
infection (when Japanese encephalitis virus is
the first flavivirus with which a person has been
infected) a rapid and potent IgM response
occurs in serum and CSF within days of infec-
tion. By day 7 most patients have raised titres.74
Attempts to isolate the virus are usually
negative in such patients. However, the failure
to mount an IgM response is associated with
positive virus isolation and a fatal outcome.68
Antibody to Japanese encephalitis virus prob-
ably protects the host by restricting viral repli-
cation during the viraemic phase, before the
virus crosses the blood-brain barrier.92 Evi-
dence from other flaviviruses suggests that it
may also limit damage during established
encephalitis by neutralising extracellular virus
and facilitating lysis of infected cells by
antibody dependent cellular cytotoxicity.93
In surviving patients immunoglobulin class
switching occurs, and within 30 days most have
IgG in the serum and CSF. Asymptomatic
infection with Japanese encephalitis virus is
also associated with raised IgM in the serum,
but not CSF.74 In patients with secondary
infection (those who have previously been
infected with a diVerent flavivirus—for exam-
ple, dengue infection or yellow fever vaccina-
tion) there is an anamnastic response to
flavivirus group common antigens.74 This
secondary pattern of antibody activation is
characterised by an early rise in IgG with a
subsequent slow rise in IgM.
CELLULAR IMMUNITY
In animal models of Japanese encephalitis, the
cellular immune response seems to contribute
to the prevention of disease during acute infec-
tion by restricting virus replication before the
CNS is invaded: athymic nude mice have
increased susceptibility to experimental infec-
tion with Japanese encephalitis virus94; transfer
of spleen cells from mice immunised with
live attenuated virus conveys immunity to
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412
infection.95 Spider monkeys, which are nor-
mally unaVected by intracerebrally inoculated
virus develop rapidly progressive encephalitis
when T cell function has been impaired by
cyclophosphamide.96
In humans infected with St Louis encephali-
tis virus (a flavivirus in the same antigenic
complex as Japanese encephalitis virus) impair-
ment of T cell function by human immuno-
deficiency virus (HIV) seems to increase the
risk of developing encephalitis.97 By analogy
with other human viral infections, including
influenza, HIV, Epstein-Barr virus, and den-
gue, cytotoxic T lymphocytes might be impor-
tant in the control and possibly clearance of
Japanese encephalitis virus.98 99 Preliminary
experimental evidence is in agreement with
this: T lymphocyte responses were character-
ised in seven convalescent patients with
Japanese encephalitis and 10 vaccine
recipients.100 Japanese encephalitis virus spe-
cific T cell proliferation (including CD4+ and
CD8+ T lymphocyte responses) was demon-
strated in both groups. Japanese encephalitis
virus specific and flavivirus cross reactive
CD4+ T lymphocytes which recognise E
protein in an HLA restricted manner were
recently demonstrated in two vaccine
recipients.101
Management
Treatment for Japanese encephalitis is support-
ive, and involves controlling convulsions and
raised intracranial pressure when they occur.
For many years corticosteroids were given, but
a double blind randomised placebo controlled
trial of dexamethasone failed to show any
benefit.52 Careful nursing care and physi-
otherapy are needed to reduce the risk of bed
sores, malnutrition, and contractures. Aspira-
tion pneumonia is a common occurrence in
patients with a reduced gag reflex. There is
currently no specific treatment for Japanese
encephalitis. Isoquinolone compounds are ef-
fective in vitro,102 and monoclonal antibodies
are apparently eVective in animal models.103 104
Interferon-á is currently the most promising
potential treatment. It is produced naturally in
the CSF in response to infection with Japanese
encephalitis virus91 and in vitro it has activity
against the virus.105 Recombinant interferon-á
has been given in open trials to a few patients
with encouraging results,106 and is currently
being assessed in a placebo controlled double
blind trial.
Prevention
Broadly speaking, measures to control Japa-
nese encephalitis include those which interfere
with the enzootic cycle of the virus, and those
which prevent disease in humans. Measures to
control breeding of Culex mosquitoes, such as
the application of larvicides to rice fields, and
insecticide spraying have proved ineVectual.10
Inactivated and live attenuated vaccines (de-
scribed below) have been used to protect swine
against the virus; however, widespread vaccina-
tion is not feasible in most settings. Residents
and travellers to endemic areas should take
personal protection to reduce the number of
Solomon, Dung, Kneen, et al
Culex bites. These include minimising outdoor
exposure at dusk and dawn, wearing clothing
that leaves a minimum of exposed skin, using
insect repellents containing at least 30%
DEET (N,N-diethyl-3 methlybenzamide) and
sleeping under bed nets. While these measures
may be possible for the short term visitor, most
are not practical for residents of endemic areas.
FORMALIN INACTIVATED VACCINE
Formalin inactivated vaccines against Japanese
encephalitis were produced in Russia, Japan,
and in the United States by Albert Sabin (later
of polio fame) during the second world war to
protect American troops in Asia.107 A similar
formalin inactivated vaccine has been manu-
factured in Japan since 1954. It is produced by
Osaka University and is available inter-
nationally under the BIKEN label. Similar vac-
cines are made by other manufacturers in
India, Japan, Korea, Taiwan, Thailand, and
Vietnam. The vaccine’s eYcacy was shown in
large double blind randomised tetanus toxoid
controlled trials in Taiwan and Thailand
involving more than 300 000 children.14
In western subjects three doses of vaccine are
required to give protective antibody levels to a
suitably high number of recipients (80%-
100%); It is given at 0, 7, and 30 days, with a
booster immunisation recommended at 1 year.
In Asian subjects two doses may be suYcient
because of prior or subsequent exposure to
Japanese encephalitis or other flaviviruses (for
example, West Nile virus, dengue virus). A
booster vaccination has been recommended at
1–2 years for those with continued exposure;
however, a recent follow up study of a cohort of
immunised adults showed persistence of anti-
body at 3 years after the initial course.108
ADVERSE REACTIONS
Japanese encephalitis vaccination is associated
with a moderate frequency of local and mild
systemic side eVects. Tenderness, redness, and
swelling has been reported in up to 20% of
vaccine recipients, and fever, headache, ma-
laise, and chills have been reported in about
10%. Because the vaccine is derived from
mouse brain there has been concern about
neurologically related side eVects. However,
the amount of mouse myelin basic protein in
the vaccine is negligible. Surveillance of United
States vaccine recipients in 1945 showed no
increase of neurological conditions above
background levels, and there were no neuro-
logical events among 44 000 Thai children
receiving vaccine in an eYcacy trial.14 In Japan,
surveillance of Japanese encephalitis vaccine
related complications between 1965 and 1973
disclosed neurological events (encephalitis,
encephalopathy, seizures, peripheral neu-
ropathy) at a rate of 1–2.3/million recipients,
which is less than reported for other virus vac-
cines. However, since 1989 a new pattern of
adverse events has been recognised among
European, American, and Australian vaccine
recipients.109 These take the form of itching,
urticaria, and occasionally angio-oedema of the
face—sometimes requiring admission to hospi-
tal and corticosteroid therapy. Many of these
 Downloaded from http://jnnp.bmj.com/ on March 10, 2015 - Published by group.bmj.com
Japanese encephalitis
reactions occurred several days after vaccina-
tion. The incidence of these reactions was esti-
mated at 2 to 10 per 1000 vaccinees, and was
more likely in those with a history of
urticaria.110 No vaccine constituent responsible
for this apparently new adverse reaction has
been identified, although some cases have been
associated with allergy to gelatin stabiliser.
WHO SHOULD BE VACCINATED?
Japanese encephalitis vaccine is recommended
for native and expatriate residents of endemic
areas, laboratory workers potentially exposed
to the virus, and for travellers spending 30 days
or more in endemic areas.111 For shorter visits,
the vaccine is only recommended if there will
be extensive outdoor activity in rural areas, or if
visiting during known epidemics.111 However,
considering the variable incidence of Japanese
encephalitis from year to year, its unpredict-
ability, and the unreliability of some epidemio-
logical data, identifying areas of epidemic
transmission is diYcult. It has been argued that
the benefit of immunisation exceeds the risk of
vaccine related adverse eVects, especially when
the devastating impact of acquiring Japanese
encephalitis is contrasted with the lesser risk of
an allergic reaction that can be aborted by drug
therapy.10 Two recent cases of the disease in
short term (<2 weeks) visitors to Bali would
support the contention that all travellers to
endemic areas should be vaccinated.106–108
LIVE ATTENUATED VACCINE
In 1988 the Chinese authorities licensed a new
live attenuated Japanese encephalitis vaccine.
This strain (SA 14–14–2) was produced by
passing the virus through weanling mice, then
culturing in primary baby hamster kidney cells.
The vaccine has been shown to be safe and
immunogenic, and has been given to over 100
million children in China. Its eYcacy was
recently demonstrated in a relatively simple
and inexpensive case-control study in which
the prevalence of immunisation was compared
between 56 cases of Japanese encephalitis and
1299 age and village matched controls.112 The
eVectiveness of one dose was 80% (95% confi-
dence intervals 44%-93%) and of two doses 1
year apart 97.5% (86%-99.6%). The vaccine’s
short term safety was recently confirmed in a
randomised trial of 26 000 children,113 and it
has been shown to be immunogenic at the
shorter dosage interval of 1 and 2.5 months,
which might facilitate its incorporation into
existing immunisation programmes.114
Future directions
Despite some successes with formalin inacti-
vated vaccination, and the promise of the new
live attenuated vaccine, Japanese encephalitis
looks likely to remain an important public
health problem into the next millennium.
Unlike smallpox and polio, for which humans
are the only host and elimination by vaccina-
tion is feasible, the enzootic nature of Japanese
encephalitis virus means that there is no possi-
bility of global eradication. The geographical
area aVected is expanding, and the 2.8 billion
people living in aVected areas will continue to
413
be exposed to the virus. Thankfully, only a
small proportion of them develops disease, but
we have little understanding of what deter-
mines who develops disease and how it will
manifest. The recent discovery of a
poliomyelitis-like presentation of Japanese en-
cephalitis virus in Vietnam raises important
questions, especially as the target for global
eradication of polio by the year 2000 ap-
proaches. Is this Japanese encephalitis virus
myelitis unique to Vietnam, or is it also impor-
tant in other areas? Has it recently arisen, or
might patients who were previously labelled as
having polio, actually have been infected with
Japanese encephalitis virus? The viral and host
factors which determine who develops disease
and the diVering clinical presentations need
further investigation. Virus isolates of varying
pathogenicity for mice occur, and small
changes in the virus envelope protein aVect
neurovirulence. Whether such diVerences are
important in humans needs to be investigated.
Considering the many cases of Japanese
encephalitis, research into antiviral drugs has
been relatively neglected. Interferon-á, which
was shown to be eVective in vitro and in animal
models nearly 15 years ago is only now being
assessed in human disease. Attention should
focus on newer antiviral drugs, and their possi-
ble role in Japanese encephalitis. Pathophysi-
ological research has suggested possible thera-
peutic avenues, even in the absence of specific
antiviral drugs. Findings from Vietnam on the
importance of seizures and raised intracranial
pressure in the disease need to be confirmed in
other settings, and intervention trials consid-
ered. Japanese encephalitis virus is expanding
across the globe at an alarming rate. New rapid
diagnostic methods should facilitate monitor-
ing the spread of the disease in locations where,
until now, the aetiology of encephalitis could
only be guessed. The environmental and
ecological factors responsible for this expan-
sion need further investigations, with a view to
controlling the spread of this fascinating and
devastating disease.
We thank our many colleagues in Southeast Asia who have con-
tributed to some of the work and ideas contained in this article.
Some of the work described was supported by the Wellcome
Trust of Great Britain.
1 Tsai TF. Factors in the changing epidemiology of Japanese
encephalitis and West Nile fever. In: Saluzzo JF, Dodet B,
eds. Factors in the emergence of arbovirus diseases. Paris:
Elselvier, 1997:179–89.
2 Solomon T. Viral encephalitis in southeast Asia. Neurological
Infections and Epidemiology 1997;2:191–9.
3 Miyake M. The pathology of Japanese encephalitis. Bull
World Health Organ 1964;30:153–60.
4 Gould EA, Zanotto PM, Holmes EC. The genetic evolution
of flaviviruses. In: Saluzzo JF, Dodet B, eds. Factors in the
emergence of arbovirus diseases. Paris: Elselvier, 1997:51–63.
5 Tsai TF, Popovici F, Carnescu C, et al. West Nile encepha-
litis epidemic in southeastern Romania. Lancet 1998;352:
767–71.
6 Anonymous. Outbeak of West Nile-like viral encephalitis:
New York, 1999. MMWR 1999;48:845–49.
7 Briese T, Jia X-Y, Huang C, Grady LJ, et al. Indentification
of a Kunjin/West Nile-like flavivirus in brains of patients
with New York encephalitis. Lancet 1999;354:1261–2.
8 Kaisre R. Tick-borne encephalitis in southern Germany.
Lancet 1995;345:463.
9 Davidson MM, Williams H, Macleod J. Louping ill virus in
man: a forgotten disease. J Infect 1991;23:241–9.
10 Innis BL. Japanese encephalitis. In: Porterfield JS, ed. Exotic
viral infections. London: Chapman and Hall, 1995:147–74.
11 Buescher EL, Schere WF. Ecological studies of Japanese
encephaltiis in Japan. IX. Epidemiological correlations and
conclusions. Am J Trop Med Hyg 1959;8:719–22.
 Downloaded from http://jnnp.bmj.com/ on March 10, 2015 - Published by group.bmj.com
414
12 Peiris JSM, Amerasinghe FP, Amerasinghe PH, et al.
Japanese encephalitis in Sri Lanka: the study of an
epidemic: vector incrimination, porcine infection, and
human disease. Trans R Soc Trop Med Hyg 1992;86:307–13.
13 Chan YC, Loh TF. Isolation of Japanese encephalitis virus
from the blood of a child in Singapore. Am J Trop Med Hyg
1966;15:567–72.
14 Hoke CH, Nisalak A, Sangawhipa N, et al. Protection
against Japanese encephalitis by inactivated vaccines. N
Engl J Med 1988;319:608–14.
15 Inactivated Japanese encephalitis virus vaccine. Reccomen-
dations of the Advisory Committee on Immunization Prac-
tises (ACIP). MMWR 1993;42(RR 1):1–14.
16 Halstead SB, Grosz CR. Subclinical Japanese encephalitis.
I. Infection of Americans with limited residence in Korea.
Am J Hyg 1962;75:190–201.
17 Huang CH. Studies of Japanese encephalitis in China. Adv
Virus Res 1982;27:71–101.
18 Grossman RA, Edelman R, Chiewanich P, et al. Study of
Japanese encephalitis virus in Chaingmai Valley, Thailand.
II Human clinical infections. Am J Epidemiol 1973;98:121–
32.
19 Vaughn DW, Hoke CH. The epidemiology of Japanese
encephalitis: prospects for prevention. Epidemiol Rev 1992;
14:197–221.
20 Umenai T, Krzysko R, Bektimorov TA, et al. Japanese
encephalitis: current worldwide status. Bull World Health
Organ 1985;63:625–31.
21 Sabin AB. Epidemic encephalitis in military personnel.
JAMA 1947;13:281–93.
22 Dickerson RB, Newton JR, Hansen JE. Diagnosis and
immediate prognosis of Japanese B encephalitis. Am J Med
1952;12:277–88.
23 Lincoln AF, Silvertson SE. Acute phase of Japanese B
encephalitis. Two hundred and one cases in American sol-
diers, Korea 1950. JAMA 1952;150:268–73.
24 Richter RW, Shimojyo S. Neurologic sequelae of Japanese B
encephalitis. Neurology 1961;11:553–9.
25 Ketel WB, Ognibene AJ. Japanese B encephalitis in
Vietnam. Am J Med Sci 1971;261:271–9.
26 Chen WR, Tesh RB, Ricco-Hesse R. Genetic variation of
Japanese encephalitis virus in nature. J Gen Virol 1990;71:
2915–22.
27 Huong VTQ, Ha DQ, Deubel V. Genetic study of Japanese
encephalitis viruses from Vietnam. Am J Trop Med Hyg
1993;49:538–44.
28 Igarashi A, Tanaka M, Morita K, et al. Detection of West
Nile and Japanese encephalitis viral genome sequences in
cerebrospinal fluid from acute encephalitis cases in
Karachi, Pakistan. Microbiol Immunol 1994;38:827–30.
29 Zimmerman MD, Scott RM, Vaughn DW, et al. Short
report: an outbreak of Japanese encephalitis in Kath-
mandu, Nepal. Am J Trop Med Hyg 1997;57:283–4.
30 Hammon WM, Tiggert WD, Sather GE, et al. Epidemio-
logic studies of concurrent “virgin” epidemics of Japanese
B encephalitis and mumps on Guam, 1947–8, with subse-
quent observations including dengue through 1957. Am J
Trop Med Hyg 1958;67:441–67.
31 Paul WS, Moore PS, Karabatsos N, et al. Outbreak of Japa-
nese encephalitis on the island of Saipan, 1990. J Infect Dis
1993;167:1053–8.
32 Anonymous. Outbreak of Hendra-like virus: Malaysia and
Singapore, 1998–9. MMWR 1999;48:265–9.
33 Paton NI, Leo YS, Zaki SR, et al. Outbreak of Nipah-virus
infection among abattoir workers in Singapore. Lancet
1999;354:1253–6.
34 Chua KB, Goh KJ, Wong KT, et al. Fatal encephalitis due to
Nipah virus among pig-farmers in Malaysia. Lancet
1999;354:1257–9.
35 Wuryadi S, Suroso T. Japanese encephalitis in Indonesia.
Southeast Asian J Trop Med Public Health 1989;20:575–80.
36 Hanna J, Ritchie S, Phillips DA, et al. An outbreak of Japa-
nese encephalitis in the Torres Trait, Australia. Med J Aust
1996;165:256–60.
37 Anonymous. Japanese encephalitis on the Australian main-
land. Communicable Disease Intelligence 1998;22:80.
38 Hanna JN, Ritchie SA, Phillips DA, et al. Japanese encepha-
litis in north Queensland, Australia. Med J Aust 1999;7:
533–6.
39 Chen WR, Ricco-Hesse R, Tesh RB. A new genotype of
Japanese virus from Indonesia. Am J Trop Med 1992;47:61–
9.
40 McMinn PC. The molecular basis of virulence of the
encephalitogenic flaviviruses. J Gen Virol 1997;78:2711–
22.
41 Heinz FX. Epitope mapping of flavivirus glycoproteins. Adv
Virus Res 1986;31:103–68.
42 Mason PW, Pincus S, Fournier MJ, et al. Japanese encepha-
litis virus-vaccinia recombinants produce particulate forms
of the structural proteins and induce high levels of protec-
tion against lethal JEV infection. Virology 1991;180:294–
305.
43 Monath TP, Heinz FX. Flaviviruses. In: Fields BN, Knipe
DM, Howley M, eds. Fields virology. 3rd ed. Philadelphia:
Lippincott-Raven, 1996:961–1034.
44 Chen Y, Maguire T, Hileman RE, et al. Dengue virus infec-
tivity depends on envelope protein binding to target cell
heparan sulphate. Nature Med 1997;3:866–71.
45 Cecilia D, Gould EA. Nucleotide changes respsonsible for
loss of neuroinvasiveness in Japanese encephalitis virus
neutralisation-resistant mice. Virology 1991;181:70–7.
46 Hasegawa H, Yoshida M, Shiosaka T, et al. Mutations in the
envelope protein of Japanese encephalitis virus aVect entry
Solomon, Dung, Kneen, et al
into cultured cells and virulence in mice. Virology
1992;191:158–65.
47 Ni H, Barrett ADT. Molecular diVerences between
wild-type Japanese encephalitis virus strains of high and
low mouse neuroinvasiveness. J Gen Virol 1996;77:1449–
55.
48 Solomon T, Thao LTT, Dung NM, et al. Clinical features of
Japanese encephalitis: prognostic and pathophysiological
significance in 50 patients. In: 7th International Congress for
Infectious Diseases. Hong Kong: International Society for
Infectious Diseases 1996:132.
49 Kumar R, Mathur A, Kumar A, et al. Clinical features and
prognostic indicators of Japanese encephalitis in children in
Lucknow (India). Indian J Med Res 1990;91:321–7.
50 Poneprasert B. Japanese encephalitis in children in northern
Thailand. Southeast Asian J Trop Med Public Health
1989;20:599–603.
51 Misra UK, Kalita J. Movement disorders in Japanese
encephalitis. J Neurol 1997;244:299–303.
52 Hoke CH, Vaughn DW, Nisalak A, et al. EVect of high dose
dexamethasone on the outcome of acute encephalitis due
to Japanese encephalitis virus. J Infect Dis 1992;165:631–7.
53 Solomon T, Kneen R, Dung NM, et al. Poliomyelitis-like ill-
ness due to Japanese encephalitis virus. Lancet 1998;351:
1094–7.
54 Kumar R, Agarwal SP, Waklu I, et al. Japanese encephalitis:
an encephalomyelitis. Indian Pediatr 1991;23:1525–33.
55 Kumar S, Misra UK, Kalita J, et al. MRI in Japanese
encephalitis. Neuroradiology 1997;39:180–4.
56 Tzeng SS. Respiratory paralysis as a presenting symptom in
Japanese encephalitis: a case report. J Neurol 1989;236:
265–9.
57 Simpson TW, Meiklehohn G. Sequelae of Japanese B
encephalitis. Am J Trop Med Hyg 1947;27:727–31.
58 Kumar R, Mathur A, Singh YD, et al. Clinical sequelae of
Japanese encephalitis in children. Indian J Med Res
1993;97:9–13.
59 Huy BV, Tu HC, Luan TV, et al. Early mental and
neurological sequelae after Japanese B encephalitis. South-
east Asian J Trop Med Public Health 1994;25:549–53.
60 Schneider RJ, Firestone MH, Edelman R, et al. Clinical
sequelae after Japanese encephalitis: a one year follow up
study in Thailand. Southeast Asian J Trop Med Public Health
1974;5:560–8.
61 Shoji H, Murakamo T, Murai I, et al. A follow-up study by
CT and MRI in 3 cases of Japanese encephalitis. Neurora-
diology 1990;32:215–19.
62 Misra UK, Kalita J, Jain SK, et al. Radiological and neuro-
physiological changes in Japanese encephalitis. J Neurol
Neurosurg Psychiatry 1994;57:1484–7.
63 Huang C-R, Chang W-N, Lui C-C, et al. Neuroimages of
Japanese encephalitis: report of 3 patients. Chin Med J
(Engl) 1997;60:105–8.
64 Misra UK, Kalita J. A comparative study of Japanese and
herpes simplex encephalitis. Electromyogr Clin Neurophysiol
1998;38:41–6.
65 Kimura K, Dosaka A, Hashimoto Y, et al. Single-photon
emission CT findings in acute Japanese. Am J Neuroradiol
1997;18:465–9.
66 Gourie-Devi M, Deshpande DH. Japanese encephalitis. In:
Prasad LS, Kulczycki LL, eds. Paediatric problems. New
Delhi: S Chand, 1982:340–56.
67 Kedarneth N, Prasad SR, Dandawate CN, et al. Isolation of
Japanese encephalitis and West Nile viruses from periph-
eral blood of encephalitis patients. Indian J Med Res 1984;
79:1–7.
67a Solomon T, Dung NM, Vaughn DW, et al. Neurological
manifestations of dengue infection. Lancet 2000 (in press).
68 Leake CJ, Burke DS, Nisalak A, et al. Isolation of Japanese
encephalitis virus from clinical specimens using a continu-
ous mosquito cell line. Am J Trop Med Hyg 1986;35:1045–
50.
69 Mathur A, Kumar R, Sharma S, et al. Rapid diagnosis of
Japanese encephalitis by immunofluorescent examination
of cerebrospinal fluid. Indian J Med Res 1990;91:1–4.
70 Desai A, Shankar SK, Ravi V, et al. Japanese encephalitis
virus antigen in the brain and its topographical distribu-
tion. Acta Neuropathol 1995;89:368–73.
71 Clark CH, Casals J. Techniques for hemagglutination
inhibition with arthropod viruses. Am J Trop Med Hyg
1958;7:561–73.
72 Bundo K, Igarashi A. Antibody-capture ELISA for detec-
tion of immunoglobulin M antibodies in sera from
Japanese encephalitis and dengue hemorrhagic fever
patients. J Virol Methods 1985;11:15–22.
73 Innis BL, Nisalak A, Nimmannitya S, et al. An enzyme-
linked immunosorbent assay to characterize dengue infec-
tions where dengue and Japanese encephalitis co-circulate.
Am J Trop Med Hyg 1989;40:418–27.
74 Burke DS, Nisalak A, Ussery MA, et al. Kinetics of IgM and
IgG responses to Japanese encephalitis virus in human
serum and cerebro-spinal fluid. J Infect Dis 1985;151:
1093–9.
75 Solomon T, Thao LTT, Dung NM, et al. Rapid diagnosis of
Japanese encephalitis by using an IgM dot enzyme immu-
noassay. J Clin Micro 1998;36:2030–4.
76 Meiyu F, Huosheng C, Cuihua C, et al. Detection of
flavivirus by reverse transcriptase-polymerase chain reac-
tion with the universal primer set. Microbiol Immunol 1997;
41:209–13.
77 Monath TP, Cropp CP, Harrison AK. Mode of entry of a
neurotropic virus into the central nervous system. Reinves-
tigation of an old controversy. Lab Invest 1983;48:399–410.
 Downloaded from http://jnnp.bmj.com/ on March 10, 2015 - Published by group.bmj.com
Japanese encephalitis
78 Myint KSA, Raengsakulrach B, Young GD, et al. Immuno-
cytochemical detection of Japanese encephalitis (JE) virus
antigen in the CNS of rhesus macaques inoculated intrana-
sally with JE virus. Am J Trop Med Hyg 1994;51(suppl):
274.
79 Johnson RT, Burke DS, Elwell M, et al. Japanese
encephalitis: immunocytochemical studies of viral antigen
and inflammatory cells in fatal cases. Ann Neurol 1985;18:
567–73.
80 Dropulie B, Masters CL. Entry of neurotropic arboviruses
into the central nervous system: an in vitro study using
mouse brain endothelium. J Infect Dis 1990;161:685–91.
81 Liou M-L, Hsu C-Y. Japanese encephalitis virus is
transported across the cerebral blood vessels by endocyto-
sis in mouse brain. Cell Tissue Res 1998;293:389–94.
82 Liu YF, Teng CL, Liu K. Cerebral cysticercosis as a factor
aggravating Japanese B encephalitis. Chinese Med J
1957;75:1010.
83 Shankar SK, Rao TV, Mruthyunjayana BP, et al. Autopsy
study of brains during an epidemic of Japanese encephalitis
in Karnataka. Indian J Med Res 1983;78:431–41.
84 Shiraki H. Encephalitis due to arboviruses: Japanese
encephalitis. In: Celers RDaJH, ed. Clinical virology: the
evaluation and management of human viral infections.
Philadelphia, PA: WB Saunders, 1970:155–75.
85 Hase T, Sumers PL, Dubois DR. Ultrastructural changes of
mouse brain infected with Japanese encephalitis virus. Int J
Exp Pathol 1990;71:493–505.
86 Zimmerman HM. The pathology of Japanese B encephali-
tis. Am J Pathol 1946;22:965–91.
87 Haymaker W, Sabin AB. Topographic distribution of lesions
in central nervous system in Japanese B encephalitis.
Nature of the lesions with report of a case on Okinawa.
Arch Neurol Psychiatry 1947;57:673–92.
88 Li ZS, Hong SF, Gong NL. Immunohistochemical study of
Japanese B encephalitis. Chin Med J (Engl) 1988;101:768–
71.
89 Liu J-L. Protective eVect of interferon á on mice
experimentally infected with Japanese encephalitis virus.
Chinese Journal of Microbiology 1972;5:1–9.
90 Ghosh SN, Goverdhan MK, Sathe PS, et al. Protective eVect
of 6-MFA, a fungal interferon inducer against Japanese
encephalitis virus in bonnet macaques. Indian J Med Res
1990;91:408–13.
91 Burke DS, Morrill JC. Levels of interferon in the plasma and
cerebrospinal fluid of patients with acute Japanese
encephalitis. J Infect Dis 1987;155:797–9.
92 Hammon WM, Sather GE. Passive immunity for arbovirus
infection. I. Artificially induced prophylaxis in man and
mouse for Japanese (B) encephalitis. Am J Trop Med Hyg
1973;22:524–34.
93 Carmenaga DL, Nathonson N, Cole GA.
Cyclophosphamide: potentiated West Nile encephalitis:
relative influence of cellular and humoral factors. J Infect
Dis 1974;130:634–41.
94 Yu WX, Wang JF, Zheng GM, et al. Response of normal and
athymic mice to infection by virulent and attenuated Japa-
nese encephalitis virus. Chinese Journal of Virology 1985;1:
203–9.
95 Jia LL, Zheng A, Yu YX. Study on the immune mechanism
of JE attenuated live vaccine (SA14-14–2 strain) in immune
inhibited mice. Chinese Journal of Immunology and Microbi-
ology 1992;12:364–4.
415
96 Nathanson N, Cole GA. Fatal Japanese encephalitis virus
infection in immunosuppressed spider monkeys. Clin Exp
Immunol 1970;6:161–6.
97 Okhuysen PC, Crane JK, Pappas J. St Louis encephalitis in
patients with human immunodeficiency virus infection.
Clin Infect Dis 1993;17:140–1.
98 Bukowski JF, Kurane I, Lai C-J, et al. Dengue virus-specific
cross-rective CD8+ human cytotoxic T lymphocytes. J
Virol 1989;63:5086–91.
99 McMichael AJ. Cytotoxic T lymphocyte specific for
influenza virus. Curr Top Microbiol Immunol 1994;189:75–
91.
100 Konishi E, Mason PW, Innis BI, et al. Japanese encephali-
tis virus-specific proliferative responses of human periph-
eral blood T lymphocytes. Am J Trop Med Hyg 1995;53:
278–83.
101 Aihara H, Takasaki T, Matsutani T, et al. Establishment
and characterization of Japanese encephalitis virus-specific,
human CD4+ T-cell clones: flavivirus cross-reactivity, pro-
tein recognition, and cytotoxic activity. J Virol 1998;72:
8032–6.
102 Takegami T, Simamura E, Hirai K-I, et al. Inhibitory eVect
of furanonaphthoquinone derivatives on the replication of
Japanese encephalitis virus. Antiviral Res 1998;37:37–45.
103 Kimura-Kuroda J, Yasui K. Protection of mice against
Japanese encephalitis virus by passive administration with
monoclonal antibodies. J Immunol 1988;15:3606–10.
104 Zhang M, Wang M, Jiang S, et al. Passive protection of
mice, goats, and monkeys against Japanese encephalitis
with monoclonal antibodies. J Med Virol 1989;29:133–8.
105 Harinasuta C, Wasi C, Vithanomsat S. The eVect of inter-
feron on Japanese encephalitis virus in vitro. Southeast Asian
J Trop Med Public Health 1984;15:564–8.
106 Harinasatu C, Nimmanitya S, Titsyakorn U. The eVect of
interferon á on two cases of Japanese encephalitis in Thai-
land. Southeast Asian J Trop Med Public Health 1985;16:
332–6.
107 Tsai TF, Yu YX. Japanese encephalitis vaccines. In: Plotkin
SA, Mortimer EAJ, eds. Vaccines. Philadelphia: WB
Saunders, 1994:671–713.
108 Gambel JM, DeFraites RF, Hoke Jr CH, et al. Japanese
encephalitis vaccine: persistence of antibody up to 3 years
after a three dose primary series. J Infect Dis 1995;171:
1074.
109 RuV TA, Eisen D, Fuller A, et al. Adverse reactions to
Japanese encephalitis vaccine. Lancet 1991;338:881–2.
110 Plesner AM, Ronne T. Allergic mucocutaneous reactions
to Japanese encephalitis vaccine. Vaccine 1997;15:1239–43.
111 Anonymous. Inactivated Japanese encephalitis virus vac-
cine. Recommendations of the Advisory Committee on
Immunization Practices (ACIP). MMWR 1993;42:1–15.
112 Hennessy S, Zhengle L, Tsai TF, et al. EVectiveness of
live-attenuated Japanese encephalitis vaccine (SA14–14–
2): a case control study. Lancet 1996;347:1583–6.
113 Liu Z-L, Hennessey S, Strom BL, et al. Short-term safety
of live attentuated Japanese encephalitis vaccine (SA14–
14–2): results of a randomised trial with 26 239 subjects. J
Infect Dis 1997;176:1366–9.
114 Tsai TF, Yong-Xin Y, Putvatan R, et al. Immunogenicity of
live attenuated SA14–14–2 Japanese encephalitis vaccine: a
comparison of 1- and 3-month immunization schedules. J
Infect Dis 1998;177:221–3.
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Japanese encephalitis

Tom Solomon, Nguyen Minh Dung, Rachel Kneen, Mary Gainsborough,

David W Vaughn and Vo Thi Khanh

J Neurol Neurosurg Psychiatry 2000 68: 405-415

doi: 10.1136/jnnp.68.4.405

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